DAT-NR1 KO mice were implanted with a bilateral cannula in the VTA to deliver specific NMDAR antagonists during a cocaine sensitization regimen, and our results have shown that sensitization can be equally blocked in DAT-NR1 KO and WT animals by simultaneous injection of an NMDAR antagonist in the VTA along with peripheral cocaine. Our experiments are now aimed at ruling out or including the mesocortical DA cell population as the mediator of VTA NMDA dependent sensitization. We are currently performing patch-clamp recordings from retrograde labeled neurons projecting to the prefrontal cortex in DAT-NR1 KO to determine if these dopamine neurons, due to low DAT levels and therefore lack of Cre, may express NMDAR currents. In addition, TH-NR1 KO animals are being generated, and if viable, will be used to determine the response to cocaine sensitization, as in these KO animals NMDAR currents will be eliminated in all dopamine cells. Possible pitfalls when using TH-NR1 animals is the unspecificity of the NR1 deletion, as NMDAR will be deleted in all cathecholaminergic brain areas. However, if TH-NR1 KO animals do not develop cocaine induced sensitization it will suggest the likelihood of an active role of the DA mesocortical projection for the initiation of sensitization.